A facile and improved synthesis of desomorphine and its deuterium-labeled analogue

Article abstract of DOI:10.1007/s00706-011-0635-y

This work describes a convenient and improved process for the synthesis of desomorphine from codeine. The proposed method affords the highly pure opiate without the aid of chromatographic purification, and provides a simple route for the synthesis of [²H₃] deuterium-labeled desomorphine.

Full text of DOI:10.1007/s00706-011-0635-y

Monatsh Chem (2012) 143:171–174
DOI 10.1007/s00706-011-0635-y
ORIGINAL PAPER
A facile and improved synthesis of desomorphine
and its deuterium-labeled analogue
•
Sankareswaran Srimurugan Chi-Ju Su
•
•
Hun-Chi Shu Kaliyappan Murugan
•
Chinpiao Chen
Received: 23 April 2010 / Accepted: 24 August 2011 / Published online: 29 September 2011
Ó Springer-Verlag 2011
Abstract This work describes a convenient and improved
process for the synthesis of desomorphine from codeine.
The proposed method affords the highly pure opiate
without the aid of chromatographic purification, and pro-
vides a simple route for the synthesis of [2H3] deuterium-
labeled desomorphine.
depression than can be caused by an equivalent dose of
morphine. However, the fact that it has abuse potential
raises the possibility that it may become a future threat [8].
Internal standards are therefore essential for the detection
and quantification of the drug in the samples of abusers.
Deuterium-labeled internal standards are particularly
effective for mass spectrometry analyses and quantification
[9]. Selective ion monitoring, which is based on combined
gas chromatography and mass spectrometry, is usually used
as a very sensitive method for estimating specific assays of
controlled substances in urine samples. It utilizes corre-
sponding site-specific deuterium-labeled compounds as
internal standards [10–12]. Many studies of the preparation
of deuterium-labeled control drugs as internal standards for
use in GC–MS analysis have been published [13–17].
Most of the synthetic routes to desomorphine (3) that are
described in the literature have low yields and involve
tedious reaction processes [18, 19]. This study describes an
improved process for the synthesis of desomorphine with
higher yield and purity ([99% by GC) without the need for
purification by column chromatography. The process was
optimized for synthesizing deuterium-labeled desomor-
phine [2H3]-3 with very high purity.
Keywords Opiates Á Desomorphine Á Deuterium Á
Controlled drugs Á Internal standard
Introduction
The active constituent of opium, i.e. morphine, is respon-
sible for its pain-relieving properties and has been used very
effectively for this purpose. Although morphine is an
extremely effective analgesic, its use has to be limited
because of certain undesirable effects of which ‘‘physical
addiction’’ is the most serious [1–3]. A considerable amount
of research has been directed towards synthesis of ana-
logues that are completely devoid of this drawback.
Desomorphine (3; Fig. 1) [4], a derivative of morphine, has
similar sedative and analgesic effects. It is around ten times
more potent than morphine with a rapid onset of action
[5–7]. Additionally, desomorphine has a short duration
of action, with relatively less nausea and respiratory
Results and discussion
Scheme 1 describes the protocol for the synthesis of deso-
morphine. A codeine-free base 2 was generated from
codeine phosphate supplied by the National Bureau of
Controlled Drugs, Taiwan. The C-14 hydroxy group of 2
was deoxygenated by converting it into a better leaving
group and then displacing with hydride [20]. Tosylation and
mesylation of codeine were therefore performed, affording
the corresponding tosylate or mesylate 4. The latter method
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0635-y) contains supplementary
material, which is available to authorized users.
S. Srimurugan Á C.-J. Su Á H.-C. Shu Á K. Murugan Á
C. Chen (&)
Department of Chemistry, National Dong Hwa University,
Soufeng, Hualien 974, Taiwan, R.O.C
e-mail: chinpiao@mail.ndhu.edu.tw
123

172
S. Srimurugan et al.
HO
MeO
HO
in desomorphine. It involves transforming the methyl
group to a carbamate [27], followed by reduction with
LiAlD4. N-Carbothoxylation of the tertiary amine of
desocodeine (6) using ethyl chloroformate gave N-carb-
ethoxydesocodeine (7) in good yield, which was converted
back to deuterium-labeled desocodeine [2H3]-6 by reflux-
ing with LiAlD4. Demethylation of [2H3]-6 with BBr3 as
described above formed d-desomorphine [2H3]-3.
HO
O
O
O
R
N
N
N
HO
R = CH3/CD3
1
2
3
Fig. 1 Structures of analgesic opiates: 1 morphine, 2 codeine, 3
desomorphine
In summary, a short and efficient route for the synthesis
of desomorphine and its deuterium analogue is described.
The process affords highly pure desomorphine without the
need for column purification, with an overall yield of 38%.
was adopted because it had a higher yield and a shorter
reaction time. However, the mesylate 4 was found to be
unstable upon storage, and was therefore used immediately
in the next step. Treatment of 4 with two equivalents of
lithium aluminum hydride in THF at room temperature for a
short time (1.5 h) afforded deoxycodeine (5) in high yield
[21]. The use of fewer LiAlH4 equivalents with a longer
reaction time or refluxing the reaction mixture, gave more
side-products, as observed by TLC.
Experimental
All reactions were carried out in anhydrous solvents. THF
was distilled from sodium-benzophenone under argon.
1
CH2Cl2 and hexane were distilled from CaH2. H NMR
spectra were obtained at 400 MHz and 13C NMR spectra
were obtained at 100.5 MHz using a Bruker Avance
400 MHz NMR spectrometer. Chemical shifts (d) are
reported in ppm relative to CDCl3 (7.26 and 77.0 ppm).
Infrared spectra were recorded using an ATI Mattson
spectrometer. An Agilent 7890AGC/5975CMS gas chro-
Hydrogenation of 5 over H2/PtO2 in a Parr shaker
(4 bar) afforded highly pure 6 in quantitative yield [22, 23].
The final demethylation of 6 was attempted using methods
that have been reported elsewhere [22, 24, 25]. A mixture
of products with low conversion of the starting material
was observed using most of the reported methods. An
efficient protocol for the high-yield demethylation of
morphine to codeine with good purity using BBr3 was
therefore attempted [26]. A modification of the established
procedure, using 1.5 equivalents of the reagent instead of
excess BBr3 (6.0 equivalents), afforded desomorphine (3)
in acceptable yield and very high purity. All reaction
products were analyzed by GC–MS and shown to be over
99% pure. The overall yield of the process was 38%, but no
column purification was required in any stage.
matograph–mass spectrometer equipped with
a FID
detector, split/splitless injector, and chemstation software
was used for this study. A DB-35MS capillary column
(30 m 9 0.25 mm i.d., film thickness 0.25 lm) in a pulsed
splitless mode was utilized for the separation of the ana-
lytes. Helium with a flow rate of 1.0 cm3 min-1 was used
as a carrier gas. The temperature program for the experi-
ments was as follows. The initial column temperature was
held at 50 °C for 1 min and then raised at 5 °C min-1 to
100 °C and maintained for 1 min and further ramped at
5 °C min-1 to a final temperature of 250 °C and held for
20 min. The temperature of injection port and transfer line
was held at 290 and 280 °C, respectively. To determine the
The synthetic route was modified to incorporate deute-
rium into desomorphine (Scheme 2). N-Methylation with
[2H3]-CH3 is a convenient method for installing deuterium
Scheme 1
O
O
O
Et3N, MsCl,
CH2Cl2, 0 oC, 1h
LiAlH4, THF,
RT, 1h
O
O
O
95 %
93 %
N
N
N
MsO
HO
2
4
5
O
HO
O
PtO2/H2 (4 bar),
MeOH, 1h
BBr3, CH2Cl2,
RT, 30 min
O
43 %
99 %
N
N
6
3
123

Synthesis of desomorphine
173
Scheme 2
O
O
O
EtOCOCl,
CHCl3, Reflux
LiAlD4, THF,
Reflux
O
O
O
O
53 %
CD3
75 %
N
N
O
N
[2H ]-
6
6
3
7
HO
BBr3, CH2Cl2,
RT, 30 min
O
43 %
CD3
N
[2H3]-3
solution was washed with CH2Cl2 and then acidified to pH
*1 with 2 M HCl. The acidic solution was again washed
with CH2Cl2 and made slightly alkaline with concentrated
(28–30%) ammonia (pH *8). The turbid solution was
extracted with CH2Cl2 (2 9 30 cm3) and the combined
organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated to afford the product as a white
solid (1.00 g, 43%); m.p.: 196 °C ([28], 188–189 °C).
retention times and characteristic mass fragments, electron
impact (EI) mass spectra of the analytes were recorded by
total ion monitoring. For quantitative analysis, the chosen
diagnostic mass fragments were monitored in the selected
ion monitoring (SIM) mode: codeine (tR = 38.6 min;
m/z = 299, 229, 162); deoxycodeine (tR = 34.7 min; m/z =
283, 229, 214); desocodeine (tR = 34.2 min; m/z = 285,
270, 228); [2H3]-desocodeine (tR = 34.2 min; m/z = 288,
273, 228); desomorphine (tR = 34.5 min; m/z = 271, 228,
214). Optical rotations were measured using a JASCO
P-1010 polarimeter at the indicated temperature using a
sodium lamp (D line, 589 nm).
N-Carboethoxydesocodeine (7, C20H25NO4)
A mixture of 1.00 g desocodeine (3.5 mmol), 2.00 cm3
ethyl chloroformate (21.1 mmol), and 0.56 g anhydrous
K2CO3 (4.0 mmol) in 100 cm3 CHCl3 was refluxed for 6 h.
After completion of the reaction (TLC, 6 h), the reaction
solution was cooled to room temperature and filtered
through a Celite bed. It was washed with 10 cm3 CHCl3
and the combined filtrate was concentrated under reduced
pressure to yield a colorless viscous liquid, which was used
directly in the next reaction without purification (0.90 g,
75%). [a]2D0 = -172.8 °cm2g-1 (c = 0.69, CH2Cl2); IR
Deoxycodeine (5)
LiAlH4 (0.73 g, 19.1 mmol) was weighed in an oven-dried
flask. Dry THF (54 cm3) was then added at 0 °C. To the
stirred slurry was added 3.60 g solid codeine mesylate
(9.6 mmol) at the same temperature in three portions over
15 min. The reaction mixture was then stirred at 0 °C for
30 min and at r.t. for 1 h. After completion of the reaction
(TLC, 1 h), the reaction mixture was cooled to 0 °C and
carefully quenched with aqueous THF. The resulting slurry
was filtered through a pad of Celite and washed with excess
EtOAc (2 9 15 cm3); the filtrate was concentrated under
reduced pressure to afford a white solid product (2.50 g,
93%), which was directly used for the next reaction without
further purification; m.p.: 80 °C ([21], 81–82 °C).
ꢀ
(KBr): m = 2,931, 1,693, 1,502, 1,432, 1,319, 1,272, 1,224,
1,130, 1,099, 937 cm-1 1H NMR (300 MHz, CDCl3,
;
mixture of rotamers): d = 6.74–6.76 (m, 2H), 6.64–6.66
(m, 2H), 4.58–4.62 (m, 2H), 4.12–4.18 (m, 2H), 3.89–4.10
(m, 1H), 3.87 (s, 3H), 2.83–3.02 (m, 1H), 2.67–2.82 (m, 2H),
2.14–2.18 (m, 1H), 2.00–2.05 (m, 1H), 1.69–1.72 (m, 2H),
1.54–1.67 (m, 2H), 1.19–1.32 (m, 5H), 0.82–0.85 (m, 1H)
ppm; 13C NMR (100.6 MHz, CDCl3): d = 155.5, 155.3,
144.1, 143.8, 129.1, 125.8, 125.6, 119.2, 119.1, 113.4,
113.3, 89.3, 61.3, 56.3, 51.4, 51.1, 42.6, 42.5, 41.9, 38.6,
34.9, 34.7, 29.1, 28.6, 24.8, 24.7, 21.3, 17.2, 17.1 ppm;
EI–MS: m/z = 343.2 (M?, 100), 227.1, 195.1.
Desomorphine (3)
A solution of 2.50 g desocodeine (8.77 mmol) in 25 cm3
CH2Cl2 was added over 2 min to a well-stirred solution of
10.53 cm3 BBr3 (1 M in CH2Cl2, 10.53 mmol) that was
maintained at temperatures in the range 23–26 °C. Stirring
was continued for further 30 min at 23–26 °C. The reaction
mixture was then poured into a well-stirred mixture of
60 cm3 ice-water and 13 cm3 of concentrated (28–30%)
ammonia. The two-phase system was kept at -5 °C for
0.5 h (with continuous stirring) and extracted with excess
of CH2Cl2 (2 9 30 cm3). The combined organic extracts
were concentrated to afford crude material, which was
extracted with 10 cm3 2 M NaOH solution. The aqueous
[2H3]-Desocodeine ([2H3]-6, C18H20D3NO2)
LiAlD4 (62 mg, 1.46 mmol) was weighed in an oven-dried
50-cm3 single neck flask at atmosphere argon. It was
cooled to 0 °C and 5 cm3 dry THF were added dropwise
with stirring over 10 min. A solution of 0.50 g N-car-
bethoxydesocodeine (1.5 mmol) in 5 cm3 THF was added
dropwise over a period of 15 min, and the resulting slurry
was warmed to room temperature and refluxed for 1 h.
123

174
S. Srimurugan et al.
After the completion of the reaction, the flask was cooled
to 0 °C, and the system was carefully quenched by adding
aqueous THF. It was then filtered over Celite, washed with
EtOAc (3 9 15 cm3) and concentrated under reduced
pressure to afford [2H3]-desocodeine (0.22 g, 53%) as a
colorless solid. M.p.: 106 °C; [a]2D0 = -86.4 °cm2g-1
(c = 0.61, CH2Cl2); IR (KBr): ꢀm = 2,929, 2,377, 2,348,
2,308, 2,227, 2,167, 2,038, 1,608, 1,502, 1,440,
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1,274 cm-1; H NMR (400 MHz, CDCl3): d = 6.71–6.73
(d, J = 8.1 Hz, 1H), 6.63–6.65 (d, J = 8.1 Hz, 1H), 4.60–
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was performed in a similar fashion as described earlier.
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2.61–2.65 (dd, J = 3.8, 12.0 Hz, 1H), 2.40–2.46 (dd,
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(100.6 MHz, CDCl3): d = 143.0, 140.4, 129.9, 125.5,
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Acknowledgments The authors thank National Bureau of Con-
trolled Drugs, Department of Health, Taiwan, Republic of China, for
financially supporting this work under contract DOH97-NNB-1002,
and National Science Council of Republic of China (NSC 96-2811-
M-259-011) for a fellowship.
123